Phenotypic screening to identify small-molecule enhancers for glucose uptake: target identification and rational optimization of their efficacy.
Angew Chem Int Ed Engl
; 53(20): 5102-6, 2014 May 12.
Article
en En
| MEDLINE
| ID: mdl-24692390
ABSTRACT
Small-molecule glucose uptake enhancers targeted to myotubes and adipocytes were developed through a phenotypic screening linked with target identification and rational optimization. The target protein of glucose-uptake enhancers was identified as a nuclear receptor PPARγ (peroxisome proliferator-activated receptor gamma). Subsequent optimization of initial hits generated lead compounds with high potency for PPARγ transactivation and cellular glucose uptake. Finally, we confirmed that the chirality of optimized ligands differentiates their PPARγ transcriptional activity, binding affinity, and inhibitory activity toward Cdk5 (cyclin-dependent kinase 5)-mediated phosphorylation of PPARγ at Ser273. Using phenotype-based lead discovery along with early-stage target identification, this study has identified a new small-molecule enhancer of glucose uptake that targets PPARγ.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Glucosa
Tipo de estudio:
Diagnostic_studies
/
Screening_studies
Límite:
Animals
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Año:
2014
Tipo del documento:
Article